Noradrenergic Signaling in the Ventral Tegmental Area (VTA) Modulates Binge-Like Ethanol Consumption and Unconditioned Aversive Responses in Male and Female Mice

Ethanol comprises innately aversive properties that may act as a deterrent to overconsumption. A growing body of literature suggests that activation of noradrenergic circuitry arising from the locus coeruleus (LC) may protect against binge-like ethanol intake in mice. Here, we provide novel evidence that both agonism of α-1 adrenergic receptors (ARs) in the ventral tegmental area (VTA), as well as chemogenetic activation of noradrenergic LC to VTA projection neurons, blunts binge-like ethanol intake in male and female mice without altering sucrose intake, locomotor activity, or anxiety-like behavior. Furthermore, we demonstrate that both chemogenetic activation of the LC → VTA circuitry and peripheral administration of the aversive agent lithium chloride induce mid-frequency vocalizations consistent with an aversion- or malaise-like state in mice. We speculate that noradrenergic VTA circuitry may play a protective role against binge drinking and may be a potential target to reduce excessive drinking before ethanol dependence.